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ACMG PRACTICE GUIDELINES
American College of Medical Genetics standards and
guidelines for interpretation and reporting of postnatal
constitutional copy number variants
Hutton M. Kearney, PhD1, Erik C. Thorland, PhD2, Kerry K. Brown, PhD3,
Fabiola Quintero-Rivera, MD4, and Sarah T. South, PhD5, A Working Group of the American College of
Medical Genetics (ACMG) Laboratory Quality Assurance Committee
Disclaimer: These ACMG Standards and Guidelines are developed primarily as an educational resource for clinical
laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards
and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and
Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and
tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure
or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific
circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to
document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is
in conformance with these Standards and Guidelines. They also are advised to take notice of the date any
particular standard or guidelines was adopted and to consider other relevant medical and scientific information
that becomes available after that date. It also would be prudent to consider whether intellectual property
interests may restrict the performance of certain tests and other procedures.
Abstract: Genomic microarrays used to assess DNA copy number are
now recommended as first-tier tests for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple
congenital anomalies. Application of this technology has resulted in the
discovery of widespread copy number variation in the human genome, both
polymorphic variation in healthy individuals and novel pathogenic copy
number imbalances. To assist clinical laboratories in the evaluation of copy
number variants and to promote consistency in interpretation and reporting
of genomic microarray results, the American College of Medical Genetics
has developed the following professional guidelines for the interpretation
and reporting of copy number variation. These guidelines apply primarily
to evaluation of constitutional copy number variants detected in the postnatal setting. Genet Med 2011:XX(XX):000 – 000.
Key Words: CNV, copy number variant, microarray, aCGH, CMA
G
enomic microarrays used to assess DNA copy number,
often referred to as chromosomal or cytogenetic/cytogenomic microarrays, are powerful clinical diagnostic tools now
recommended as first-tier tests for the postnatal evaluation of
individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies.1,2 Most genomic
From the 1Fullerton Genetics Center, Mission Health System, Asheville, North
Carolina; 2Department of Laboratory Medicine and Pathology, Mayo Clinic College
of Medicine, Rochester, Minnesota; 3Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; 4Department of
Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, California; and 5ARUP Laboratories, Departments
of Pediatrics and Pathology, University of Utah, Salt Lake City, Utah.
Hutton M. Kearney, PhD, Fullerton Genetics Center, Mission Health System, 267
McDowell Street, Asheville, NC 28803. E-mail: [email protected].
The authors declare no conflict of interest.
DOI: 10.1097/GIM.0b013e3182217a3a
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microarrays used in clinical practice, including array-based
comparative genomic hybridization and single-nucleotide polymorphism-based platforms, provide genome-wide coverage for
detection of chromosomal imbalances at a much higher resolution than a conventional cytogenetic analysis (e.g., G-banded
karyotype). The ability to examine the genome at this high
resolution has resulted in the discovery of widespread copy
number variation in the human genome, both polymorphic
variation in healthy individuals and novel pathogenic copy
number imbalances.
A copy number variant (CNV) is defined as a segment of
DNA at least 1 kb in size that differs in copy number compared
with a representative reference genome. The term “CNV” does
not imply clinical significance; therefore, a qualifier such a
pathogenic CNV or benign CNV is necessary for clear communication of clinical relevance. In addition, the term “CNV” does
not imply relative dosage. Copy number loss (deletion) or copy
number gain (duplication) must be specified to clarify the nature
of a CNV.
Although genomic regions rich in low copy repeat sequences
(or segmental duplications) may result in commonly recurring
CNVs usually well described in the medical literature, many
CNVs represent rare variation. In many cases, the interpreting
geneticist can assess the genomic content of the CNV, correlate
with established clinical literature, and provide an interpretation
that is unambiguous and consistent with the interpretation derived from multiple laboratories.3 However, given the presence
of benign CNVs within the genome and the continual discovery
of novel CNVs, assessing the clinical significance of CNVs
found in a clinical setting can be challenging.4,5 Accordingly,
when the CNV is extremely rare or limited clinical literature is
available, interpretation and reporting practices may vary
among laboratories.6 To assist clinical laboratories in the evaluation of CNVs and to promote consistency in interpretation
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and reporting of genomic microarray results, the American
College of Medical Genetics (ACMG) has developed the following professional guidelines for the interpretation and reporting of copy number variation. In addition, these guidelines may
serve as a reference for referring clinicians, so they may better
understand the complexity of CNV interpretation and communicate these findings to patients and families appropriately.
These guidelines apply primarily to evaluation of constitutional CNVs detected in the postnatal setting. Although these
guidelines are relevant for CNVs detected during prenatal testing, interpretation and reporting of prenatal CNVs require additional considerations outside the scope of this document.
These guidelines do not apply to CNVs representing acquired
mutations in neoplasia. In addition, this document does not
address analytical validation; therefore, the recommendations
assume that the laboratory is confident the CNV represents true
biological copy number variation in the patient. Although these
guidelines attempt to cover common issues encountered during
evaluation of CNVs, there are many CNVs with unique characteristics, and no algorithm will be applicable to all findings.
RECOMMENDATIONS FOR SYSTEMATIC
EVALUATION AND CLINICAL INTERPRETATION
OF CNVs
Familiarization with well-established contiguous gene
syndromes
Approaching a large segmental deletion or duplication by
interrogation of single genes within the interval may not reveal
the associated syndromic deletion/duplication. It is necessary
that recurrent and clinically characterized deletion/duplication
syndromes, any associated low copy repeat sequences, and
critical regions be recognized and carefully mapped before
offering clinical interpretations of microarray data. The following represent helpful reviews but do not substitute for continuing education and monitoring of the rapidly expanding medical
literature: OMIM,7 GeneReviews,8 DECIPHER,9 and recently
published reviews.10,11
Consideration of CNV size
Although generalizations drawn between CNV size and significance hold true as a general rule, it is clear that very large
CNVs can be benign in nature,12–15 and very small CNVs can be
clinically significant. It is, therefore, recommended that any size
restriction for inclusion of a CNV in a clinical report be based
on the laboratory’s consideration of the performance characteristics of the array used and generation of a reasonable amount of
clinical follow-up, rather than assumptions regarding clinical
significance.
Consideration of genomic content in CNV interval
This is by far the most relevant interpretive consideration and
is fairly broad in scope. One should consider whether the CNV
contains unique, gene-rich sequence or is void of genes and/or
is primarily comprised of repetitive elements or pseudogenes.
The gene content should be carefully scrutinized for documented and relevant clinical association.
When considering the potential phenotypic effect due to copy
number gain or loss of a gene or group of genes, one should
investigate whether the genes in the interval are reported to be
dosage sensitive and associated with clinical disorders. It is
useful and convenient to review entries in the OMIM database7;
however, it is also prudent to search for recent publications that
may not have been incorporated into the OMIM review.
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Given that CNV breakpoints are not precisely mapped due to
gaps in probe coverage, it is important to consider all the genes
in the maximum CNV interval before presuming a CNV to be
clinically benign. Further evaluation may be necessary to clarify
the genomic content of the CNV for appropriate clinical interpretation.
Genes with reported pathogenic mutations in the medical
literature. The nature of the disease-associated mutations
should be carefully interrogated to ensure relevance for the
CNV in question. Although this list is not comprehensive, the
following examples illustrate the need for a clear understanding
of genetic mechanisms: (1) a gene associated with a clinical
phenotype due to haploinsufficiency may have no phenotype
associated with a copy number gain. (2) Dominant disorders
often result from specific gain of function mutations rather than
dosage imbalance; therefore, CNVs involving such genes may
either have no clinical relevance or result in an entirely different
phenotype (e.g., gain of function/activating mutations in
FGFR1 result in skeletal dysplasias, whereas deletions/loss of
function mutations are associated with Kallmann syndrome16).
(3) Copy number gains involving only part of a gene may result
in gene disruption or altered coding sequence and should not be
dismissed without further investigation when involving genes
with reported haploinsufficiency.17 (4) Single-copy deletions of
genes associated with recessive disease may only suggest carrier status for the condition. (5) Small CNVs involving only
intronic sequence may have no effect on gene function.
Genes with no reported mutations in the medical
literature. Avoid, or use great caution when, inferring a pathogenic role for a gene based solely on predicted gene function or
functions characterized in model organisms or in vitro studies.
This inference is speculative until well characterized in the
human population.
No genes in interval. Generally, it is acceptable to adopt a
laboratory policy not to report these CNVs, as there is no
relevant literature to interrogate. An exception might be made if
the CNV exceeds a size cutoff established by the laboratory or
is located in close proximity to a well-characterized region with
clear relevance to the reason for referral (e.g., a deletion bordering a holoprosencephaly locus in a patient with a holoprosencephaly indication18 –20).
Comparison of CNV with internal and external
databases
We recommend that laboratories performing array-based assessment of copy number track their experience and document
pathogenic CNVs, CNVs of uncertain significance, and CNVs
that have been determined to represent benign variation. A CNV
that is well documented as a benign variant in the performing
laboratory, or in peer reviewed published reports or curated
databases, likely needs little additional investigation provided
the CNV is periodically reinvestigated to ensure that no new
data have emerged contradicting this classification. A CNV with
which the laboratory has no prior experience should be carefully
compared with publicly available databases of copy number
variation in the general population, such as the Database of
Genomic Variants.21,22 Note that we have used the term general
population rather than normal population, as it is clear that
“normal” is relative to the phenotype in question, and some of
the individuals represented in large population databases have
no phenotypic data available (e.g., HapMap).
Considerations when comparing patient data with CNVs
reported in general population databases include:
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ACMG guidelines for CNV interpretation
finding in the general population might exclusively represent a
copy number gain. If the CNV in question overlaps the same
region, but is a copy number loss, a pathogenic outcome cannot
be excluded. The opposite situation also applies. Similarly, a
CNV observed commonly as a heterozygous deletion in the
general population may have a pathogenic outcome when present in a homozygous state.
patient but which overlap a smaller interval with clearly established clinical significance. Although the full clinical effect of
the patient’s CNV is not known, the pathogenic nature of the
CNV is not in question.
With the exception of well-established cytogenetic heteromorphisms, this category will include most cytogenetically visible alterations (⬎3–5 Mb). In the absence of clearly defined
syndromic loci within the interval, this inference should be
made with caution.
Size of the reported benign CNV relative to the CNV in
question. One should ensure that the CNV reported in the
Uncertain clinical significance
Dosage of copy number imbalance reported in the
general population studies. The CNV reported as a benign
general population includes the same gene content as the CNV
being interrogated. Different array platforms represented in the
public databases can lead to differences in the reported size of
identical CNVs. Notably, many of the benign CNVs reported
from earlier bacterial artificial chromosome-based microarray
studies represent size overestimates.23
Sex of individual in database relative to patient sex. This
consideration is particularly important for X-linked CNVs in
males, as many of the reported benign variants are seen in
females who may be nonmanifesting carriers of the condition.
In addition, consider that contributors to these databases may
have excluded the sex chromosomes from analysis; therefore,
CNVs mapping to the X and Y chromosomes may be underrepresented.
Validity of the CNV reported in general population
databases. The majority of CNVs reported from large popu-
This represents a fairly broad category and will include
findings that are later demonstrated to be either clearly pathogenic or clearly benign. However, if at the time of reporting,
insufficient evidence is available for unequivocal determination
of clinical significance and the CNV meets the reporting criteria
established by the laboratory, the CNV should be reported as a
CNV of uncertain clinical significance.
When warranted, one may provide evidence for the likelihood that the CNV is pathogenic or benign, provided any such
speculation is well supported in the report, and the uncertainty
of this classification is still communicated. Three categories for
classification of uncertain variants are suggested and examples
provided below. These examples do not cover all scenarios, as
each CNV will have unique considerations requiring clinical
judgment.
●
lation studies have not been experimentally validated; therefore,
CNVs reported in a single study or through use of a single
microarray platform should be interpreted with caution.
Clinical characterization of “normal” individuals. One
should consider the extent of clinical characterization of individuals represented in the database. Each population series is
selected based on defined criteria, usually outlined in the primary reference. Consider how these individuals were selected
for inclusion and how likely it is that the clinical phenotype
presented in the patient of interest might be present in the
“normal” population. Factors such as incomplete penetrance,
variable expressivity, age of onset, and parent of origin imprinting effects need to be considered before classification of a CNV
as benign in all instances. CNVs occurring with relatively high
frequency in the general population and in multiple publications
may be interpreted with more confidence as benign in nature. Of
note, many publications use the same reference set (e.g., HapMap); therefore, a CNV represented in multiple publications
may represent the same individual studied multiple times.
Recommended categories of clinical significance
Using the guidelines outlined earlier for systematic investigation of a CNV for clinical significance, the interpreting laboratory geneticist should assign any CNV reported in the patient
to one of three main categories of significance. It is recommended that consistent terminology for these categories be used
in clinical reporting to facilitate unambiguous communication
of clinical significance throughout the medical community.
Pathogenic
The CNV is documented as clinically significant in multiple
peer-reviewed publications, even if penetrance and expressivity
of the CNV are known to be variable.
This category includes large CNVs, which may not be described in the medical literature at the size observed in the
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●
Uncertain clinical significance; likely pathogenic: for example: (1) The CNV is described in a single case report but
with well-defined breakpoints and phenotype, both specific
and relevant to the patient findings. (2) A gene within the
CNV interval has a very compelling gene function that is
relevant and specific to the reason for patient referral.
Inferences made from data derived solely from model
systems should be made with discretion and in general, are
discouraged. Such speculation is strongly discouraged for
scenarios with nonspecific indications (e.g., intellectual
disability) and/or limited evidence regarding gene function
(e.g., only information available for gene is documented
neuronal expression).
Uncertain clinical significance; likely benign: for example: (1) The CNV has no genes in interval (but is reported
because it exceeds a size criterion that may be established
by the laboratory). (2) The CNV is described in a small
number of cases in databases of variation in the general
population but does not represent a common polymorphism.
Uncertain clinical significance (no subclassification): for
example: (1) The CNV contains genes, but it is not known
whether the genes in the interval are dosage sensitive. (2)
The CNV is described in multiple contradictory publications and/or databases, and firm conclusions regarding
clinical significance are not yet established.
Benign
The CNV has been reported in multiple peer-reviewed publications or curated databases as a benign variant, particularly if
the nature of the copy number variation has been well characterized (e.g., copy number variation of the salivary amylase
gene24) and/or the CNV represents a common polymorphism.
To qualify as a polymorphism, the CNV should be documented
in ⬎1% of the population. It is important to carefully consider
dosage of the CNV documented as a benign variant, given, for
example, that duplications of some regions may be benign,
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whereas deletions of the same interval may have clinical relevance.
REPORTING GUIDELINES FOR GENOMIC COPY
NUMBER MICROARRAYS USED IN THE
POSTNATAL CONSTITUTIONAL SETTING
The following guidelines describe those elements of the
clinical report that are necessary to specify the precise identity
of a CNV and clearly communicate the clinical significance of
the microarray results. Other required elements of a clinical
report (e.g., methodology and relevant disclaimers) are outlined
in detail in the ACMG Laboratory Standards and Guidelines;
section E13.
Reporting criteria
The laboratory report should include a description of the
criteria used to review the data (e.g., CNV size restrictions) and
the criteria used for inclusion of a CNV in the report. Laboratories may choose not to disclose benign CNVs, especially those
that represent common polymorphisms. If benign CNVs are
listed in the report, they should meet the same analytical performance criteria used in the laboratory to evaluate suspected
pathogenic CNVs.
Description of position, size, and relative gain or loss
for each CNV detected
Each CNV included in the laboratory report should be described with the elements below. Current nomenclature from the
International System for Cytogenetic Nomenclature should be
included in the report but should not serve as a substitute for a
clear description of the imbalance for clinical professionals
unfamiliar with International System for Cytogenetic Nomenclature conventions.
●
●
●
Cytogenetic location (chromosome number and cytogenetic band designation).
Dosage (e.g., copy number gain or loss) with CNV mechanism specified when understood (e.g., single-copy deletion, tandem duplication). Assessment of mechanism will
usually require additional testing methodology.
CNV size and linear coordinates with genome build specified. When applicable, particularly when gene content of
the CNV is unclear, minimum/maximum coordinates
should be provided.
Clear statement of clinical significance
Each reported CNV should be accompanied by a clear statement of significance as outlined in these recommendations. The
evidence in support of this interpretation should be summarized
and appropriate references provided.
Designation of genes in CNV interval
To the extent feasible, genes involved in a CNV should be
specified in the laboratory report. For large imbalances, particularly those with well-established clinical significance, it is
acceptable to provide only the name of the corresponding syndrome and/or the most clinically relevant genes in the interval.
For CNVs of uncertain significance, it is suggested that all
RefSeq genes in the interval be included in the report, when
feasible, to facilitate periodic reviews of relevant medical literature. The incorporation of links to websites that list the genes
in a particular interval is not recommended because the links
may not faithfully direct the clinician to the appropriate gene
content in the future, particularly when genome builds change.
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When only one or few representative genes are specified in the
report, it is suggested that the total number of genes in the CNV
interval be provided to allow for perspective of the total gene
content.
Recommendation for appropriate clinical follow-up
When pathogenic CNVs or CNVs of uncertain clinical significance are found, the laboratory report should include recommendations for genetic consultation/counseling, any necessary cytogenetic characterization of the CNV, and evaluation of
relevant family members. In addition, when a CNV is determined to have uncertain clinical significance, the report may
include a recommendation for continued surveillance of the
medical literature for new information, which could later clarify
the clinical significance of the finding. The responsibility for
continuing monitoring of the medical literature for a specific
patient lies primarily with the physician with an ongoing patient
relationship.25
SPECIAL CONSIDERATIONS REGARDING
REPORTING OF UNANTICIPATED CLINICALLY
SIGNIFICANT FINDINGS UNRELATED TO THE
REASON FOR REFERRAL
In rare cases, CNVs may be found in a patient which (1)
reveal carrier status for a recessive condition, (2) are diagnostic
or predictive of a presymptomatic condition or a symptomatic
condition with unrecognized clinical presentation, or (3) are
associated with an increased risk of neoplasia. In general, these
findings are unanticipated and unrelated to the patient’s reason
for referral for a genomic screen. It is not possible to construct
a whole genome microarray platform that purposefully avoids
interrogation of any loci associated with the aforementioned
cases, especially as many of the findings will be part of a large
CNV involving multiple contiguous genes. Therefore, referring
clinicians must have a clear understanding of the potential for
these discoveries, and patients/families should be duly informed
before test ordering. A formal informed consent process is
strongly recommended. In rare situations, creation of unique
CNV-reporting categories (e.g., carrier-presumed unaffected)
may be necessary for unambiguous reporting.
Reporting carrier status for recessive conditions
It is recognized that detection of some CNVs, particularly
deletions, will reveal carrier status for recessive disorders in the
deletion interval. Comprehensive reporting of heterozygous recessive mutations is outside the scope of the intended use of
these tests and, in general, is not recommended. Reports should
clearly state that recessive carrier status may not be disclosed,
and that any clinical concern for recessive disorders should be
communicated to the reporting laboratory for appropriate consideration. There are some situations when disclosure of recessive mutations may be considered. Individual laboratories may
choose to adopt specific disclosure policies for recessive conditions.
1. Well-characterized recessive disorders, for which carrier
frequency is reasonably high in the patient population
and/or carrier screening is commonly available (e.g., cystic fibrosis). In such cases, there may be justification for
reporting carrier status to provide opportunity for reproductive counseling and potential additional testing in the
proband or relevant family members. It should be recognized that these disclosures will represent serendipitous
findings, and no claim should be made to the ordering
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clinician or patient that this test will detect carrier status
for any condition.
2. Recessive disorders with clinical features consistent with
the patient’s reason for referral. In such cases, recommendation for further molecular testing for this disorder may
be warranted. This should be restricted to well-described
recessive disorders with clear clinical consequence. The
report should clearly state the recessive nature of the
condition and that the CNV is not diagnostic of affected
status without confirmation of a second mutation.
Reporting mutation status for adult onset/
presymptomatic or undiagnosed conditions
Some CNVs, although unrelated to the patient’s reason for
referral, may be clearly diagnostic of a presymptomatic or
clinically undetected condition (e.g., male infertility due to
deletions involving the AZF region on the Y chromosome26).
Given that it is impossible to construct a predefined list of all
possible diagnoses to allow the patient to consent specifically to
the interrogation/reporting of each disorder, it is our general
recommendation that CNVs associated with presymptomatic
conditions be reported to facilitate early access to medical care.
Individual laboratories may wish to adopt nondisclosure policies for specific conditions. Any such policies should be stated
in the laboratory report.
Reporting CNVs associated with risk of neoplasia
Deletions that include a known or putative tumor suppressor
gene should be carefully considered. Tumor suppressor genes
with clearly pathogenic germline mutations and information on
penetrance, lifetime risk, tumor spectrum, and clinical management (e.g., RB1, TP53, and APC) should be discussed in the
report, regardless of the indication for study.27 Speculation
regarding putative tumor suppressor genes should be avoided,
particularly in the absence of well-characterized germline mutations in humans and in the case of genes where tumor suppressor functions have only been shown in animal or in vitro
models.
SPECIAL CONSIDERATIONS FOR REEVALUATION
OF SIGNIFICANCE BASED ON DATA FROM
OTHER FAMILY MEMBERS
When CNVs are found to have uncertain clinical significance, it may be informative to determine whether the CNV was
inherited or represents a de novo mutation. Although this is a
very relevant line of evidence by which to gauge clinical significance, it is important to stress that it is difficult, and often
imprudent, to attribute clinical significance based on the inheritance pattern of a CNV in a single family. It is only through
ascertainment of significantly large families with multiple affected and unaffected family members segregating a given CNV
or ascertainment of multiple individuals with the same CNV
that a true measure of clinical significance can be confidently
assessed. For this reason, the ACMG strongly supports efforts
to collect and curate deidentified patient data from clinical
studies to facilitate rapid and unambiguous assessment of the
clinical significance of CNVs.2,9,28
In the absence of a large data series, a cautious inference
should be made based on the limited family information available. Addendums to the original interpretation, based on information from evaluation of family members, should be appropriately communicated with disclaimers summarizing the
following points. Each CNV and each family will have unique
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ACMG guidelines for CNV interpretation
considerations, and these investigations require significant communication between laboratorians and referring clinicians.
De novo CNVs
When a CNV is shown to represent a de novo mutation in the
proband, this is generally taken as evidence supporting pathogenicity, particularly if the CNV was suspected to have clinical
significance based on other lines of evidence, such as gene
content. Nonpaternity may complicate this interpretation and, as
such, should be disclaimed in the report. Specific testing to
confirm paternity is not recommended unless there is a compelling clinical reason to make this assessment and explicit informed consent is obtained.
Because many regions of the genome have significantly
elevated mutation rates, some CNVs may indeed be de novo
mutations yet represent findings with no associated clinical
consequence.29
If only one parent is available for follow-up, and the CNV is
not found in the parent available for study, no additional inference regarding clinical significance can be made.
Inherited CNVs
When a CNV is found in a parent or other relevant family
member, there are numerous caveats one should consider.
Rarely can a conclusive inference be made based on the inheritance pattern observed in a single family. The carrier parent and
other relevant family members should have a thorough medical
evaluation for the presence or absence of the clinical features
present in the proband. When this information is not provided to
the laboratory, this should be disclaimed in the report and a
recommendation for correlation with parental clinical features
made.
Parent is affected. In general, this may be cautiously taken as
evidence that supports the CNV as the cause of the clinical
features. This observation may be coincidental, however, as the
CNV and clinical trait may be inherited independently by
chance. When available, other family members may be evaluated to determine whether the CNV continues to segregate in
concordance with the clinical phenotype.
Parent is unaffected. In general, this may be taken as evidence that supports the CNV as unrelated to the clinical features
and likely benign. Special considerations that preclude confident inference and may only be well defined after ascertainment
of multiple families include the following:
●
●
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●
●
Incomplete penetrance: The CNV may be pathogenic but
nonpenetrant in the carrier parent.
Variable expressivity: The carrier parent may have subclinical features that will later be shown to be in the
spectrum of the disorder caused by the CNV.
Parent of origin imprinting effects: The CNV region may
be imprinted, such that the disorder only manifests when
inherited from a particular sex (and the carrier parent is not
manifesting the disorder because of chance inheritance).
Second mutation not detectable by microarray: The proband may be manifesting a recessive disorder (e.g., a
deletion may be inherited from an unaffected carrier parent
and an undetectable mutation inherited in a gene within the
interval from the other parent). Alternatively, the proband
may have one or more “modifier” genes/DNA elements
not present in the unaffected parent.
Mosaic CNV in parent: The CNV may not be present in all
tissues of the parent, and therefore, the parent may not
manifest all clinical features associated with the CNV.
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●
CNV in proband is not identical in size to that seen in parent:
Rarely, CNVs have been found to undergo further modification (e.g., expansion of deletion) when transmitted from carrier parent to affected child.30 When the parental studies are
performed by an alternative methodology such as fluorescence in situ hybridization, this rare possibility cannot be
excluded.
Special consideration for X-linked CNVs: When an Xlinked CNV in a male is found in an unaffected carrier
mother, one should consider whether the mother is a nonmanifesting carrier. Studies of X-inactivation may be informative, but not all X-linked disorders exhibit skewed
X-inactivation in carrier females. It may be more informative to seek other male relatives in the maternal family.
CONCLUDING REMARKS
With the expanding availability of whole-genome testing methodologies, clinical genetics professionals must be prepared to interpret unexpected findings and report them appropriately, not only
with consideration of clinical relevance but also with consideration
of social, ethical, and legal responsibilities. The interpretation of
the clinical relevance of copy number variation is complex and is
the practice of medicine. As evident from the numerous considerations outlined in this document, there is no one formula or algorithm for CNV interpretation that will substitute for adequate
training in clinical genetics and sound clinical judgment. We,
therefore, recommend that the reporting of clinical genomic microarrays be performed by individuals with appropriate professional training and certification (American Board of Medical Genetics-certified clinical cytogeneticists, American Board of
Medical Genetics-certified clinical molecular geneticists, or American Board of Medical Genetics/American Board of Pathologycertified molecular genetic pathologists). In addition, given the
complexity of this interpretation and the different laboratory methodologies necessary for CNV characterization and evaluation of additional family members, the ideal laboratory setting for this testing is
one with both cytogenetic and molecular genetic expertise.
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